Healthy Aging and Latent Infection with CMV Lead to Distinct Changes in CD8+ and CD4+ T-Cell Subsets in the Elderly
Introduction
It is generally recognized that the function of the immune system declines with age [1, 2] leading to increased susceptibility to infectious disease and endangering the protective effect of vaccination [3, 4]. Because of the involution of the thymus, changes in the composition of the T-cell repertoire are among the most striking features of immunosenescence. A decreased thymic output of naïve T cells leads to low naïve T-cell numbers in the peripheral blood as well as in the lymph node tissue, whereas there is an increase in the numbers of memory and effector T cells [5, 6]. These changes seem to be more pronounced in the CD8+ than in the CD4+ T-cell pool. Longitudinal studies suggest that decreased CD4+/CD8+ ratios, together with increased numbers of CD57+and CD28− T cells and poor T-cell proliferation are part of the “immunologic risk phenotype” (IRP), which correlates with subsequent 2-year mortality in the elderly [7, 8]. The pronounced accumulation of CD28−CD57− effector cells that produce large amounts of IFNγ may also contribute to the proinflammatory status typically observed in old age [9].
Chronic inflammation is believed to support the development and perpetuation of age-related diseases such as Alzheimer disease and atherosclerosis [10, 11]. Recently it has been suggested that long-term infection with Cytomegalovirus (CMV), a human β-herpes virus, accelerates age-related alterations in the composition of the T-cell repertoire [12, 13, 14]. 60–100% of the adult population is infected with CMV, which establishes a life-long latency with recurrent reactivations in the infected host. CMV triggers the expansion of CMV-specific T-cell clones, which occupy a lot of immunologic space and thus lead to reduced diversity. In all age groups, latent CMV-infection is typically accompanied by a decrease in naïve T cells and the simultaneous accumulation of effector T cells [15, 16, 17, 18], but the changes are most pronounced in elderly persons with a positive CMV serology [12]. CD8+ cells are more affected by CMV than their CD4+ counterparts [19]. Aging and latent CMV infection thus induce similar changes in the T-cell pool.
As a relatively large percentage of the elderly population is infected with CMV and no attention is being paid by many authors of biogerontologic studies to distinguish between CMV-positive and CMV-negative persons [5, 20], it remains unclear which of the described changes result from CMV and which result from the aging process. The epidemiologic situation in Austria with approximately 30% of the elderly being CMV-negative has enabled us to compare phenotypic properties of CD8+ and CD4+ T cells in large cohorts of CMV-positive and CMV-negative elderly persons and to perform correlations between the different T-cell subsets in these two cohorts.
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Blood Donors and Samples
Heparinized venous blood was obtained from 251 apparently healthy elderly persons (mean age 67.6 ± 6.5 years, range 59–91 years; 135 female [54%]). A medical history was obtained and individuals with malignancies, acute diseases, or advanced stages of severe chronic diseases, such as chronic inflammatory disease, atherosclerotic disease, congestive heart failure, poorly controlled diabetes mellitus, renal or hepatic disease, or chronic obstructive pulmonary disease, as well as persons under
Results and discussion
Several different definition criteria for human T-cell subpopulations have been suggested in the literature. Generally, a combination of two surface markers—in most cases CD45RA and one additional marker, such as CD28, CD62L, CD95, or CCR7—is judged to be sufficient to distinguish between naïve, memory, and effector T cells [5, 21, 22]. For this study expression of CD45RA and CD28 was used for classification of T cells. Although we realize that the coexpression of those two surface markers does
Acknowledgment
This work was supported by the Austrian Science Fund (Project S 9308-B05).
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B.W. and L.L contributed equally to this paper.